Over the past two decades there has been an exponential increase in our understanding of the neurobiological basis of drug addiction, yet this country continues to be plagued by drug related crimes and deaths. More research is needed to further characterize the cellular adaptations that take place in response to chronic drug exposure in order to develop pharmacological strategies to combat drug addiction. This research proposal will provide essential information about the medial prefrontal cortex (mPFC), a brain region that is increasingly recognized as an integral part of the circuitry of drug abuse, and thereby further our understanding of this disease. The first aim will be to determine, using in vivo extracellular recording and microiontophoresis, if the response of mPFC neurons to iontophoretic glutamate and dopamine is altered in rats repeatedly treated with cocaine. My preliminary data demonstrate increased responsiveness to glutamate and decreased responsiveness to dopamine after repeated amphetamine, and it is important to determine if amphetamine and cocaine similarly affect the mPFC. The second aim will investigate adaptations in active and passive membrane properties of mPFC neurons after repeated cocaine and amphetamine treatment using in vitro current clamp techniques in brain slices. This will provide evidence for the basis of the changes observed in the first experiment. The third aim will utilize the whole- cell dissociated neuron configuration to directly observe whether specific dopamine and glutamate receptors have undergone adaptations in response to repeated cocaine or amphetamine administration. This experiment will control for synaptic input by isolating the neurons and thereby provide direct evidence for changes in receptor-mediated responses.